Aging results in changes in the composition and function of articular cartilage. The focus of this research is to characterize changes in turnover (synthesis and degredation) of components of hyaline articular cartilage matrix and synovial fluid with age and osteoarthritis (OA). In the finial analysis, it is an imbalance in the regulation of matrix synthesis and/or degradation that results in the loss of articular cartilage and leads to OA (1-4). The general objective of this project it to develop and validate kinetic assays (kinetic biomarkers) of turnover rates of articular cartilage and synovial fluid glycosaminoglycans (GAG), collagen, or collagen derived peptides and chondrocytes in vivo in rodents for ultimate use in drug development, clinical trials and patient care in OA. Specifically, our objectives are (1) to evaluate a newly developed stable isotope/ mass spectrometric method for measuring articular cartilage and synovial fluid turnover rates of the GAG's hyalurenic acid (HA) and chrondroitin-sulfate (CS) in rats and in an animal model of OA (aging guinea pigs). (2) to evaluate a newly developed stable isotope / mass spectrometric method for measuring turnover rates of articular cartilage collagen and synovial fluid collagen-derived peptides in rats and an animal model of OA (aging guinea pigs). (3) to evaluate changes in chrondrocyte cell proliferation with age and OA in the rat and guinea pig. (4) to compare kinetic measurements of these joint protective biochemical constituents (GAG's collagen and its breakdown products, chondrocytes) from different sampling sites (articular cartilage, synovial fluid plasma) in order to understand and interpret changes in these kinetic biomarkers. (5) To compare kinetic measures of these joint protective constituents to histological and static biochemical markers of OA in the guinea pig model. In summary, we propose to develop and test kinetic biomarkers of the major protective compoments of the joint space (GAG's, collagen and chrondrocytes) and to correlate these measures with histologic markers of OA. These tools may allow significant advances in our basic understanding of the biology of the extracellular matrix in the joint space, with potential application to the prevention and treatment of arthritic disorders.